The long term objective of this proposal is to gain insight into mechanisms of cell- mediated immunity to infectious agents in humans, with particular emphasis on the generation of Th1 cytokine responses required for resistance to intracellular pathogens. Leprosy, caused by the intracellular pathogen M. leprae, presents as a clinical/ immunologic spectrum, providing an attractive model for investigating the regulation of immune responses to infection. Using leprosy as a model, the investigators propose to investigate mechanisms by which microbial antigens and cytokines regulate human Th1 responses. First, they hypothesize that VP6+ T cells, the predominant T cell in resistant lesions, selectively stimulates Th1 cytokine responses. They propose to investigate the mechanism by which this M. leprae antigen stimulates Th1 responses, by identifying the antigen, determining the cytokine pattern it elicits in leprosy patients and the MHC class II alleles involved in presentation to T cells. Second, they hypothesize that M. leprae lipoproteins have adjuvant activity in stimulating Th1 responses. They propose to investigate the mechanism by which microbial lipoproteins contribute to the induction of IL-12 in human infectious disease, by identifying and expressing M. leprae lipoproteins and measuring their ability to differentially induce IL-12 and I L-10 release from monocytes derived from leprosy patients. Experiments will be designed to ascertain whether the M. leprae signal sequence can adjuvant proteins to stimulate Th1 responses. Third, they hypothesize that a specific set of cytokines regulates IL-12RP2 expression and therefore determines the balance of Th1 vs. Th2 responses at the site of infection. They propose to investigate the mechanism by which IL-12 responsiveness is regulated by determining the cytokines that upregulate and downregulate IL-12RP2 and the mechanism by which IL-18 synergizes with IL-12 in augmenting M. leprae-induced T-cell production of IFN-gamma. The studies they propose are intended to provide a comprehensive analysis of the determinant of Th1 responses in humans in relation to a model of human infectious disease. Such insights, they would hope, would provide new avenues for development of immunomodulatory treatments for a variety of human infectious diseases.